Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide variety of cellular responses, such as proliferation, cytoskeletal organization and migration, adherence- and tight junction assembly, and morphogenesis. S1P can bind with members of the endothelial cell differentiation gene family (EDG receptors) of plasma membrane-localized G protein-coupled receptors. To date, five members of this family have been identified as S1P receptors in different cell types, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6) and S1P5 (EDG-8). S1P can produce cytoskeletal re-arrangements in many cell types to regulate immune cell trafficking, vascular homeostasis and cell communication in the central nervous system (CNS) and in peripheral organ systems.
It is known that S1P is secreted by vascular endothelium and is present in blood at concentrations of 200-900 nanomolar and is bound by albumin and other plasma proteins. This provides both a stable reservoir in extracellular fluids and efficient delivery to high-affinity cell-surface receptors. S1P binds with low nanomolar affinity to the five receptors S1P1-5. In addition, platelets also contain S1P and may be locally released to cause e.g. vasoconstriction. The receptor subtypes S1P1, S1P2 and S1P3 are widely expressed and represent dominant receptors in the cardiovascular system. Further, S1P1 is also a receptor on lymphocytes. S1P4 receptors are almost exclusively in the haematopoietic and lymphoid system. S1P5 is primarily (though not exclusively) expressed in central nervous system. The expression of S1P5 appears to be restricted to oligodendrocytes in mice, the myelinating cells of the brain, while in rat and man expression at the level of astrocytes and endothelial cells was found but not on oligodendrocytes.
S1P receptor modulators are compounds which signal as (ant)agonists at one or more S1P receptors. The present invention relates to modulators of the S1P5 receptor, in particular agonists, and preferably to agonists with selectivity over S1P1 and/or S1P3 receptors, in view of unwanted cardiovascular and/or immunomodulatory effects. It has now been found that S1P5 agonists can be used in the treatment of cognitive disorders, in particular age-related cognitive decline.
Although research is ongoing to develop therapeutics that can be used to treat age related cognitive decline and dementia, this has not yet resulted in many successful candidates. Therefore, there is a need for new therapeutics with the desired properties.
Description Of The Invention
It has now been found that spiro-cyclic amine derivatives of the formula (I)
                wherein        R1 is selected from                    cyano,            (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkyl each optionally substituted with CN or one or more fluoro atoms,            (3-6C)cycloalkyl, (4-6C)cycloalkenyl or a (8-10C)bicyclic group, each optionally substituted with halogen or (1-4C)alkyl,            phenyl, biphenyl, naphthyl, each optionally substituted with one or more substituents independently selected from halogen, cyano, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (1-6C)alkoxy optionally substituted with one or more fluoro atoms, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl optionally substituted with phenyl which may be substituted with (1-4C)alkyl or halogen,            phenyl substituted with phenoxy, benzyl, benzyloxy, phenylethyl or monocyclic heterocycle, each optionally substituted with (1-4C)alkyl optionally substituted with one or more fluoro atoms,            monocyclic heterocycle optionally independently substituted with halogen, (1-6C)alkyl optionally substituted with one or more fluoro atoms, (3-6C)cycloalkyl, or phenyl optionally substituted with (1-4C)alkyl or halogen,            and            bicyclic heterocycle optionally substituted with halogen or (1-4C)alkyl optionally substituted with one or more fluoro atoms;                        —Y—(Cn-alkylene)-X-is a linking group wherein                    Y is attached to R1 and selected from a bond, —O—, —CO—, —S—, —SO—, —SO2—, —NH—, —CH═CH—, —C(CF3)═CH—, —C≡C—, —CH2—O—, —O—CO—, —CO—O—, —CO—NH—, —NH—CO—, and trans-cyclopropylene;            n is an integer from 0 to 10; and            X is attached to the phenylene/pyridyl moiety and selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, —CO—, —CH═CH—, and trans-cyclopropylene;                        R2 is H or independently selected from one or more substituents selected from halogen, (1-4C)alkoxy and (1-4C)alkyl optionally substituted with one or more fluor atoms; and        R3 is (1-4C)alkylene-R4 wherein the alkylene group may be substituted with one or more halogen atoms or with (CH2)2 to form a cyclopropyl moiety, or R3 is (3-6C)cycloalkylene-R4, —CH2-(3-6C)cycloalkylene-R4, (3-6C)cycloalkylene-CH2—R4 or —CO—CH2—R4, wherein R4 is —OH, —PO3H2, —OPO3H2, —COOH, —COO(1-4C)alkyl or tetrazol-5-yl;        Q is a bond or —O—;        —W-T- is selected from —CH═CH—, —CH2—CH2—, —CH2—O—, —O—CH2—, —O—CH2—CH2— and —CO—O—;        R5 is H or independently selected from one or more halogens;        Z is CH, CR2 or N; and        A represents a morpholine ring structure or a 5-, 6- or 7-membered cyclic amine;or a pharmaceutically acceptable salt, a solvate or hydrate thereof or one or more N-oxides thereof, display affinity for S1P receptors. In particular, compounds of the invention show selective affinity for the S1P5 receptor over the S1P1 and/or S1P3 receptor(s).        
In the prior art, structures of spiroindoline derivatives are disclosed showing some similiarties to the structures of the compounds of the present invention, e.g. in WO 2005063745. However, those compounds are modulators of the Mas receptor. There is no suggestion or teaching that the spiroindoline compounds of WO 2005063745 may display affinity for S1P receptors.
The compounds of the invention are modulators of the S1P receptor, in particular of the S1P5 receptor. More specifically, the compounds of the invention are S1P5 receptor agonists. The compounds of the invention are useful for treating, alleviating and preventing diseases and conditions in which (any) S1P receptor(s)—in particular S1P5—is (are) involved or in which modulation of the endogenous S1P signaling system via any S1P receptor is involved. In particular, the compounds of the present invention may be used to treat, alleviate or prevent CNS (central nervous system) disorders, such as neurodegenerative disorders, in particular—but not limited to—cognitive disorders (in particular age-related cognitive decline) and related conditions, Alzheimer's disease, (vascular) dementia, Nieman's Pick disease, and cognitive deficits in schizophrenia, obsessive-compulsive behavior, major depression, autism, multiple sclerosis and pain, etc. Preferably, the compounds of the present invention may be used to treat, alleviate or prevent cognitive disorders (in particular age-related cognitive decline) and related conditions.
In an embodiment of the invention, the compounds have formula (I) wherein R3 is selected from —(CH2)2—OH, —CH2—COOH, —(CH2)2—COOH, —(CH2)3—COOH, —CH2—CHCH3—COOH, —CH2—C(CH3)2—COOH, —CHCH3—CH2—COOH, —CH2—CF2—COOH, —CO—CH2—COOH, 1,3-cyclobutylene-COOH, —(CH2)2—PO3H2, —(CH2)3—PO3H2, —(CH2)2—OPO3H2, —(CH2)3—OPO3H2, —CH2-tetrazol-5-yl, —(CH2)2-tetrazol-5-yl and —(CH2)3-tetrazol-5-yl. Preferred R3 groups are selected from —(CH2)2—COOH, —CH2—CHCH3—COOH, —CH2—C(CH3)2—COOH, —CHCH3—CH2—COOH, —CH2—CF2—COOH, —CO—CH2—COOH and 1,3-cyclobutylene-COOH. Most preferred is —(CH2)2—COOH.
In another embodiment, Q is a bond.
In another embodiment, the compounds have formula (I) wherein R2 is H, methyl, chloro or fluoro. In further embodiments, R2 is H.
In a further embodiment of the invention, Z is CH or CR2.
In another embodiment, the compounds have formula (I)—W-T- is selected from —CH2—O—, —O—CH2—, —O—CH2—CH2— and —CO—O—. In preferred embodiments, —W-T- is —O—CH2—.
Further, in an embodiment of the invention, in the group —Y—(Cn-alkylene)-X-, Y is selected from a bond, —O—, —CO—, —CH═CH—, —C(CF3)═CH—, —C≡C—, and trans-cyclopropylene; n is an integer from 0 to 6. Preferably, Y is selected from a bond, —O—, —CH═CH—, —C≡C—, and trans-cyclopropylene. In further embodiments, X is selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, —CO—, —CH═CH— and trans-cyclopropylene. Preferably, X is selected from a bond, —O—, —S—, —SO—, —SO2—, —NH—, and —CO—. In preferred embodiments, the group —Y—(Cn-alkylene)-X- is selected from —CH2—O—, —CH2—S— and —CH═CH— and particular is —CH2—O—.
In certain embodiments of the invention R1 is (1-4C)alkyl and Y is a bond, n is an integer selected from 1 to 6 and X is —O— or a bond. In further embodiments, R1 and —(CH2)n— together are a linear hexyl, heptyl or octyl group.
In other embodiments of the invention, R1 is selected from
(1-4C)alkyl, cyclohexyl, cyclohexenyl, biphenyl optionally substituted with halogen,
phenyl optionally substituted with one, two or three substituents independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, trifluoromethyl, trifluoromethoxy, and cyclopropyl optionally substituted with phenyl,
thienyl, pyridyl, tetrahydropyranyl, each optionally substituted with halogen, (1-4C)alkyl, cyclopropyl or phenyl optionally substituted with halogen, and indolyl, dihydrobenzofuranyl and benzdioxanyl, each optionally substituted with halogen or (1-4C)alkyl. In preferred embodiments of the invention, R1 is selected from phenyl, optionally substituted with one or more substituents independently selected from halogen, (1-4C)alkyl, cyclopropyl and trifluoromethyl. Further preferred, R1 is 2,6-dichlorophenyl.
In further embodiments of the invention, R5 is H.
In preferred embodiments of the invention, A represents a piperidine structure.
In another embodiment, the compounds of the invention have the structure (II)

Compounds of the invention may suitably be prepared by methods available in the art, and as illustrated in the experimental section of this description. Some novel and useful intermediates have been found for the preparation of the compounds of this invention. They are further embodiments of the invention. Thus, another embodiment of the invention is a compound of the formula (III)
wherein Br is attached at one of the sites indicated with an asterisk.
Also, an embodiment of the invention is a compound of the formula (IV)
wherein OH is attached at one of the sites indicated with #, and wherein, if OH is at the position indicated with 1, the compound may be independently substituted with (1-4C)alkyl or halogen selected from F or Cl at one or both positions indicated with 2; and W-T is —O—CH2— or —CH2—CH2—; and A represents a morpholine ring structure or a 5- or 6-membered cyclic amine. Compounds of formula (III) are useful in the preparation of compounds of the formula (I) wherein —W-T- is —O—CH2— and compounds of formula (IV) in the preparation of compounds of the formula (I) wherein —W-T- is —O—CH2— or —CH2—CH2—.
According to a further embodiment of this invention, a very efficient process for the preparation of a compound of formula (I) wherein R2 is H or one or two substituents selected from fluoro, (1-4C)alkyl and (1-4C)alkoxy; —W-T- is —O—CH2— and Z is CH or CR2, is a process, comprising an intramolecular Heck cyclization step wherein a compound of formula (V),
wherein A′ represents a 5-, 6- or 7-membered cyclic amine with a double bond at the carbon atom indicated with an arrow, P1 is a protecting group selected from —CO2-benzyl and —CO2-(1-4C)alkyl (preferably —CO2-benzyl), Bn is benzyl and the BnO-group may be attached at one of the sites indicated with #, is converted in a suitable solvent at elevated temperature (e.g. in N-Methyl-2-pyrrolidone (NMP) at 140° C.), in the presence of silver carbonate (preferably in 1-2 molar amounts with regard to the amount of compound V) and Herrmann-Beller catalyst (in 1-10 mol %, preferably 3-6 mol %) into a compound of formula (VI),
wherein A″ represents a 5-, 6- or 7-membered cyclic amine with a double bond at a position shifted one or (transiently) two positions—depending on the position of the nitrogen atom in the ring—with regard to ring A′, whereafter further process steps follow (such as first deprotection and reduction to produce a compound according to formula (IV)) to produce a compound of formula (I).
The term halogen refers to fluoro, chloro, bromo, or iodo. Preferred halogens are fluoro and chloro, and in particular chloro.
The terms (1-6C) and (1-4C)alkyl mean a branched or unbranched alkyl group having 1-6 and 1-4 carbon atoms, respectively, for example methyl, ethyl, propyl, isopropyl and butyl. A preferred alkyl group is methyl.
The term (1-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, wherein the alkyl moiety is as defined above. A preferred alkoxy group is methoxy.
The terms (1-4C)alkylene and (Cn-alkylene) mean a branched or unbranched alkylene group having 1-4 or n carbon atoms, respectively, for example methylene, —CHCH3—, —C(CH3)2—, —CHCH3CH2—, and the like. In the definition of R3 which is (1-4C)alkylene-R4, one or more carbon atoms in the alkylene group may (amongst others) independently be substituted with (CH2)2 to form a cyclopropyl moiety, meaning to form a R3 group such as

The term (2-4C)alkynyl means a branched or unbranched alkynyl group having 2-4 carbon atoms, wherein the triple bond may be present at different positions in the group, for example ethynyl, propargyl, 1-butynyl, 2-butynyl, etc.
The terms 5-, 6- or 7-membered cyclic amine as used in the definition of formula (I) refer to pyrrolidinyl, piperidinyl and hexamethyleneiminyl structures, respectively.
The term (3-6C)cycloalkyl means a cyclic alkyl group having 3-6 carbon atoms, thus cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Preferred are cyclopentyl and cyclohexyl.
The term (4-6C)cycloalkenyl means a cyclic alkenyl group having 4-6 carbon atoms and comprising one or two double bonds, for example cyclohexenyl.
The term (3-6C)cycloalkylene means a cyclic alkyl group having two attachment points. Preferred is 1,3-cyclobutylene, having the structure

The term (8-10C)bicyclic group means a fused ring system of two groups selected from aromatic and non-aromatic ring structures having together 8-10 carbon atoms, for example—and in particular—the indane group.
The term monocyclic heterocycle encompasses monocyclic heteroaryl groups and non-aromatic heteromonocyclic groups, for example furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, morpholinyl, and the like.
The term bicyclic heterocycle encompasses bicyclic heteroaryl groups and non-aromatic heterobicyclic groups, for example indolyl, indazolyl, isoindolyl, indolizinyl, benzimidazolyl, imidazothiazolyl, imidazopyridinyl, benzfuranyl, dihydrobenzofuranyl, benzdioxanyl, quinolinyl, isoquinolinyl, quinolizinyl, tetrahydroisoquinolinyl, and the like.
With reference to substituents, the term “independently” means that the substituents may be the same or different from each other in the same molecule.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
Compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
Isotopically-labeled compound of formula (I) or pharmaceutically acceptable salts thereof, including compounds of formula (I) isotopically-labeled to be detectable by PET or SPECT, also fall within the scope of the invention. The same applies to compounds of formula (I) labeled with [13C]—, [14C]—, [3H]—, [18F]—, [125I]—or other isotopically enriched atoms, suitable for receptor binding or metabolism studies.
The term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. They can be prepared in situ when isolating and purifying the compounds of the invention, or separately by reacting them with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.
The compounds of the invention may be administered enterally or parenterally. The exact dose and regimen of these compounds and compositions thereof will be dependent on the biological activity of the compound per se, the age, weight and sex of the patient, the needs of the individual subject to whom the medicament is administered, the degree of affliction or need and the judgment of the medical practitioner. In general, parenteral administration requires lower dosages than other methods of administration which are more dependent upon adsorption. However, the dosages for humans are preferably 0.001-10 mg per kg body weight. In general, enteral and parenteral dosages will be in the range of 0.1 to 1,000 mg per day of total active ingredients.
Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference “Remington, The Science and Practice of Pharmacy” (21st edition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing) the compounds may be compressed into solid dosage units, such as pills or tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension or emulsion.
For making dosage units, e.g. tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like, is contemplated. In general, any pharmaceutically suitable additive which does not interfere with the function of the active compounds can be used.
Suitable carriers with which the compounds of the invention can be administered include for instance lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. Compositions for intravenous administration may for example be solutions of the compounds of the invention in sterile isotonic aqueous buffer. Where necessary, the intravenous compositions may include for instance solubilizing agents, stabilizing agents and/or a local anesthetic to ease the pain at the site of the injection.
Pharmaceutical compositions of the invention may be formulated for any route of administration and comprise at least one compound of the present invention and pharmaceutically acceptable salts thereof, with any pharmaceutically suitable ingredient, excipient, carrier, adjuvant or vehicle.
By “pharmaceutically suitable” it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
In an embodiment of the invention, a pharmaceutical pack or kit is provided comprising one or more containers filled with one or more pharmaceutical compositions of the invention. Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals products, which notice reflects approval by the agency of manufacture, use, or sale for human or veterinary administration.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described in this document.
The following examples are intended to further illustrate the invention in more detail.
Any novel intermediate as disclosed herein is a further embodiment of the present invention.